serum marker
Transcript
serum marker
4th AISF POST-MEETING COURSE “Unmet Clinical Needs in Hepatology” Auditorium, Centro Congressi Frentani Course Directors: M. Fraquelli, Milan and G. Missale, Parma Noninvasive diagnostic tools for staging liver disease: serological markers Fabio Marra Dipartimento di Medicina Interna Università di Firenze Chronic liver diseases: Markers of disease progression Imaging: US, CT, MRI Serum Markers Stiffness HVPG Liver Biopsy: 1:50,000 of liver tissue Progression of chronic hepatitis and the METAVIR score F0 No fibrosis F1 Fibrosis without septa F2 Few septa F3 F4 Numerous Numerous septa septa NO cirrhosis WITH cirrhosis “SIGNIFICANT” FIBROSIS CIRRHOSIS “SIMPLE” STEATOSIS IDENTIFICATION OF PATIENTS WITH NAFLD STEATOHEPATITIS DIFFERENTIATION OF NAFLD FROM NASH EVALUATION OF FIBROSIS CIRRHOSIS Hepatic decompensation HEPATOCELLULAR CARCINOMA DEATH What we would like to have from a noninvasive tool 1. Diagnostic accuracy >0.8 for advanced fibrosis 2. Diagnostic accuracy >0.9 for cirrhosis 3. Ability to detect major changes in fibrosis (e.g. >2 METAVIR stages) 4. Correlate with long-term clinical outcomes 5. Applicability across different types of liver diseases 6. Known profile in control subjects 7. Possibility to be combined with other staging modalities to build an algorithm Gressner et al., World J Gastroenterol 2009; 28:2433 Mann & Marra, J Hepatol 2010; 52:949 Currently available serum markers Indirect markers Direct markers Combination markers Indirect markers of liver fibrosis Alterations in liver function that do not necessarily reflect extracellular matrix metabolism e.g.: platelet count AST INR γGT bilirubin albumin cholesterol Pinzani et al., Nat Clin Pract Gastroenterol Hepatol. 2008;5:95 Predicting clinical outcomes with standard laboratory tests in chronic hepatitis C Ghany et al., Gastroenterology 2010;138:136 Ghany et al., Gastroenterology 2010;138:136 Direct markers of liver fibrosis Tests that reflect the actual extracellular matrix turnover within the liver: e.g.: Procollagen III N-terminal peptide Type IV collagen Hyaluronic acid YKL-40 Matrix metalloproteases (MMPs) Tissue inhibitors of metalloproteases (TIMPs) Pinzani et al., Nat Clin Pract Gastroenterol Hepatol. 2008;5:95 ELF panel in NASH 12. # # ELF Score * * 10. 8. indeterminate avoid bx incorrectly 0 1 2 3 4 Fibrosis Stage (Kleiner) avoid bx correctly Guha et al. Hepatology 2008;47:455 Nobili et al. Gastroenterology 2009;136:160 Serum Fibrosis Markers, Fibrosis Stage, and Liver Collagen Content Stage 3 Collagen .0205 6 .0112 6 .0521 Some DIRECT fibrosis markers correlate better with the presence of cirrhosis than with hepatic collagen content Fontana et al., Hepatology 2008;47:789 Biochemical markers: interpretative issues “SPECTRUM BIAS” Over-representation of extreme stages (F0-F4) leads to higher sensitivity and specificity “DISCORDANT CASES”: Failure of the marker or failure of the biopsy? Biochemical markers: interpretative issues 1.- MILD/NO FIBROSIS vs. SIGNIFICANT FIBROSIS: MEDIAN AUC = 0.77 2.- CIRRHOSIS vs. NON CIRRHOSIS: MEDIAN AUC = 0.87 Inaccuracy of biopsy affects marker perfomance When errors in the diagnostic test and the gold standard are independent, the observed sensitivity and specificity of the diagnostic test will be underestimated Mehta et al., J Hepatol 2009;50:36 Algorythms? SAFE biopsy for significant fibrosis (> F2) Castera et al., J Hepatol 2010;52:191 The Castera algorythm for significant fibrosis Castera et al., J Hepatol 2010;52:191 In search for a better standard Performance of serum markers in alcoholic liver disease <0.32 >0.32, <0.58 >0.58 AUROC 0.83±0.03 Clinical outcomes as “reference standard” for biomarker development Naveau et al., Hepatology 2009;49:97 The ELF panel predicts decompensation after OLT Carrion et al., Gastroenterology 2010;138:147 ELF test can predict clinical outcomes Parkes et al., Gut 2010;59:1245 Parkes et al., Gut 2010;59:1245 Genes instead of biochemical markers? A 7 gene signature identifies the risk of developing cirrhosis during chronic hepatitis C Huang et al., Hepatology 2007;46:297 Marcolongo et al., Hepatology 2009; General considerations on serum markers of fibrosis Minimal (F0-F1) vs. significant (≥ F2) fibrosis: Detection of advanced (≥F3) fibrosis: Detection of cirrhosis: ☺ ☺ Stepwise differentiation of fibrosis stages: Fibrogenic process monitoring: Selection of patients to be biopsied ☺ ☺ Schuppan & Afdhal, Lancet 2008;371:838 Biopsy Clinical evaluation Imaging Patient categorization Follow-up with noninvasive markers Serum markers Unstable Fibroscan Repeat biopsy Stable Assessment of fibrosis progression and regression in different disease stages HVPG Stage at liver biopsy Biopsy (TJLB?) + morphometry Liver stiffness Liver stiffness Biochemical markers Biochemical markers? COMPENSATED CIRRHOSIS F0 F1 F2 F3 F4 or HVPG > 5 mmHg HVPG < 10 mmHg The need for a ‘dynamic’ serum marker 1. Not for cross-sectional staging or diagnosis 2. Sensitive to rapid changes in fibrogenesis and/or fibrolysis 3. Possibly related to ECM turnover 4. Specific for a given chronic liver disease Massimo Pinzani Umberto Arena Francesco Vizzutti Stefania Moscarella Cristina Stasi Giacomo Laffi Stefano Colagrande